Polycystic ovarian syndrome (PCOS) is a condition that afflicts certain women. Hormonally, the disease may be characterized by an elevation in serum androgens. This elevation is thought to be the proximate cause for the PCOS phenotype of hyperandrogenism (acne and hirsutism) which typifies these patients, as well as possibly contributing to features of central adiposity and insulin resistance. The elevation of serum androgens, along with the hallmark phenotype of anovulation and infertility, has been traced to an elevation in serum luteinizing hormone (LH) levels, increased LH pulse frequency, and/or increased serum LH/follicle stimulating hormone (FSH) ratio (See Hall J E, J Endocrinol Invest. 1998 October; 21(9):602-11).
At the time of filing there are no approved treatments for PCOS. “Off-label” therapies currently prescribed are aimed at eliminating the symptoms of androgen excess. First-line treatment of PCOS is usually the oral contraceptive pill (OCP) for women in whom fertility is not immediately desired. However, approximately half of these patients fail to achieve adequate control of their androgenic symptoms with an OCP and require add-on anti-androgen therapy. Anti-androgen therapy is most commonly delivered as high-dose spironolactone, which carries the risk of potentially harmful electrolyte derangement. GnRH analogues are used as the next line of therapy to reduce androgen levels, but given their marked potency they often induce chemical menopause, and therefore require add-back hormonal therapy. In addition to treatment with a therapy to reduce androgen levels, metformin may be administered as it is believed to improve menstrual regularity and fertility (as well as insulin resistance). However, data on its efficacy in these endpoints is inconclusive. For women trying to conceive, additional treatment with clomiphene (+/− metformin) improves conception rates, but with the associated risks of ovarian hyperstimulation and multiple pregnancies.
Therefore, in light of current “off-label” symptom-driven therapy with limited efficacy and notable side effects, there is a need for an approach that specifically targets the underlying hypothalamic-pituitary-gonadal (HPG) pathophysiology of PCOS and modulates LH pulsatility, with the goal of affording disease modification and concomitant symptom relief without significant adverse effects.